Fms-like tyrosine kinase 3 (FLT3), also known as Cluster of Differentiation antigen 135 (CD135), Fetal liver kinase-2 (Flk2) and Stem cell Tyrosine Kinase 1 (STK1) is a human protein (Uniprot ID: P36888) encoded by the human gene FLT3 (HGNC ID: 3765). This protein is specifically appearing on the surface of hematopoietic progenitor cells after they cease to be hematopoietic stem cells related to FLT3 expression. FLT3 regulates the maturation processes in order to develop them into functional blood cells, especially to develop properly functioning lymphocytes, alias T-cells and B-cells. The hematopoietic progenitor cells are multipotent cells, and the dysregulation of their differentiation processes often results pathologic conditions. FLT3 is one the most important regulators of this cellular maturation process, therefore mutations or overexpression of this protein are associated with several types of blood cell malignancies, including acute myeloid leukemia. As more and more information has been gathered about FLT3's role as an oncogene, FLT3's Internal Tandem Duplications (ITD) type of mutation is by now considered as a disease-specific ‘driver’ mutation. FLT(ITD) is a mutation that is a crucial turning point-like factor that moves differentiation and proliferation processes toward the initiation and progression of acute myeloid leukemia in a disease-specific way. The unique expression pattern of the mutated protein makes it a highly promising target in terms of developing really targeted and protein-specific signal transduction therapies.
FLT3 is a member of receptor tyrosine kinases class III. This class's domain structure significantly differs from the other classes' and the class contains only a few members. The kinase domain of FLT3 is relatively different compared to the mainstream targeted Tyrosine Kinases This fact indicates that the potent inhibitors of FLT3(ITD) are having a rather selective profile among Receptor Tyrosine Kinases. The effectiveness and the selectivity has been proven by in vitro biochemical assays, cellular viability assays and using a wide kinase selectivity panel.
As it was mentioned above, the styryl quinazoline compounds according to the present invention also can be applied as antibacterial agents (having bactericidal or bacteriostatic activity) for the prevention and/or treatment of bacterial infectious diseases such as meningitis of bacterial origin, gastroenteritis of bacterial origin, E. coli and Staphylococcus saprophyticus caused Urinary Tract Infections (UTI), E. coli, Shigella and Campylobacter associated Hemolytic-Uremic Syndrome (HUS), infected peritonitis, infectious mastitis, bacteraernia (bacteria caused sepsis), E. coli, Klebsiella, Pseudomonas, B. fragilis and Enterococcus caused cholecystitis, and common types of pneumonia.
Pathogenic bacteria are a major cause of human death and disease and cause infectious diseases—besides inflammation based pathogenic states mentioned above—such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. Bacterial infections may be treated with antibiotics (antibacterial agents), which are classified as bactericidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth.
Escherichia coli (E. coli, named after Theodor Escherich) is a Gram-negative, facultatively anaerobic, rod-shaped bacterium of the genus Escherichia that is commonly found in the lower intestine of endothermic organisms.
Most E. coli strains are harmless, but certain serotypes are pathogenic to humans or domestic animals. Virulent strains of E. coli are the dominant causes of various diseases; such as meningitis, gastroenteritis and UTI and less often can cause HUS, peritonitis, mastitis, bacteraernia and gram-negative pneumonia. Certain strains of E. coli produce also potentially lethal toxins, e.g. Enterotoxigenic E. coli (ETEC), Enteropathogenic E. coli (EPEC), Enteroinvasive E. coli (EIEC), Enterohemorrhagic E. coli (EHEC), Enteroaggregative E. coli (EAEC) which are causative agents of diarrhea and other gastrointestinal symptoms, and Uropathogenic E. coli (UPEC) which causes urinary tract inflammation and infection. There are also some E. coli strains that contain a polyketide synthase (PKS) genomic island whose function is to encode multiple PKSs, a multi-enzymatic machinery that produces a genotoxic substance, named colibactin. This substance can promote tumorigenesis by DNA damage.